Sickle cell disease (SCD) is a complex genetic blood disorder characterized by abnormal hemoglobin, leading to complications and reduced life expectancy. Established therapies in the SCD market include DROXIA (hydroxyurea), ENDARI (L-glutamine oral powder), ADAKVEO (crizanlizumab-tmca), OXBRYTA (voxelotor), and others. OXBRYTA, a pioneering inhibitor of HbS polymerization, received US approval for treating SCD in individuals aged ≥4 years and European approval for hemolytic anemia in those aged ≥12 years. It was the first oral therapy targeting the root cause of SCD, offering a convenient administration route. 

Osivelotor (formerly GBT021601) shares a similar mechanism of action as OXBRYTA. Osivelotor has demonstrated improved pharmacokinetics, potentially achieving higher Hb occupancies at lower doses compared to OXBRYTA. This improvement could reduce treatment frequency and enhance clinical outcomes.

Preliminary data from Part A of a 3-part Phase II/III study (NCT05431088) are presented at the EHA 2024 conference. Part A is a 12-week dose-finding study of oral osivelotor in patients with SCD (HbSS/HbSβ0 genotype) aged 18– 65 years. The primary endpoint was change from baseline (BL) in Hb at W12. Secondary endpoints included ektacytometry (Oxygenscan) to assess RBC deformability as a function of partial pressure of oxygen, expressed as elongation index.

At data cutoff of June 20, 2023, 80% (28 out of 35 patients) completed the 12-week treatment period. Hemoglobin (Hb) improvements from baseline were noticeable from the first week and persisted through Week 12. At week 12, mean increases in Hb (g/dL) were 2.63 for the 100-mg group and 3.27 for the 150-mg group. Reductions from baseline were also observed in indirect bilirubin and reticulocytes, with no increasing trend in erythromycin at Week 12. Ektacytometry results showed an increase in median elongation index (EI) and a decrease in median point of sickling (PoS) from baseline to week 12. Specifically, EImax increased from 0.37 to 0.53 in the 100-mg group and from 0.42 to 0.50 in the 150-mg group. PoS (mmHg) decreased from 37.8 to 20.8 and from 32.5 to 15.3 in the 100-mg and 150-mg groups, respectively. 

Regarding safety, treatment-emergent adverse events (TEAEs) were reported in 20 patients (57.1%). The most frequent TEAEs included headache, upper respiratory tract infection, diarrhea, arthralgia, nausea, and urticaria. Grade 1-2 TEAEs were experienced by 40% of patients. There were no Grade 3-5 TEAEs related to the drug. Serious adverse events (SAEs) were reported by 6 out of 35 patients, and 2 patients discontinued treatment due to adverse events.

Notably, Part A study's limitations, including its open-label design and small patient population, will be mitigated in Part B through a placebo-controlled design and the planned enrollment of around 330 adult and adolescent participants.

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KOL insights

“The initial findings from Part A of this Phase II/III study indicate that the loading and daily doses of osivelotor administered over 12 weeks were well tolerated among adults with sickle cell disease. Moreover, the study demonstrated significant increases in mean hemoglobin levels alongside improvements in markers of hemolysis. GBT021601 has the potential for higher Hb occupancies at lower doses than voxelotor and could potentially reduce treatment burden and improve clinical outcomes.” – MD, United States.

Conclusion 

Sickle cell disease is the most prevalent genetic blood disorder in the United States, affecting over 100,000 individuals. Despite the potential of current treatments, concerns persist about their long-term effects in both adults and children. To address these gaps, major players such as Pfizer (Osivelotor), Forma Therapeutics/Novo Nordisk (etavopivat), Novo Nordisk (NDEC), Pfizer (GBT-601), Agios Pharmaceuticals (mitapivat), Editas Medicine (EDIT-301), and others are advancing their therapies through early and late-stage development.

Osivelotor is being developed by Pfizer, which in a 2022 transaction purchased Global Blood Therapeutics (USD 5.4 billion deal), the company that had originally created osivelotor. With This OXBRYTA added to Pfizer’s portfolio of blood disorder therapies. Osivelotor is the next-generation successor of OXBRYTA, which might provide better therapeutic efficacy at lower dosages. 

Initial findings from Part A of the Phase II/III study on osivelotor, presented at a recent conference, indicate that loading and daily doses over 12 weeks were well tolerated by adults with SCD. Results so far demonstrate significant increases in average hemoglobin levels alongside improvements in markers of hemolysis. Although direct measurement of oxygen delivery was not conducted, indicators such as erythropoietin levels and vaso-occlusive crises (VOCs) did not suggest impairment. Ektacytometry data indicated enhanced red blood cell deformability and delayed HbS polymerization. These findings support continued clinical investigation of osivelotor as a potential therapy for SCD. 

However, Part A of the study had certain limitations, including an open-label design without a control group and a relatively small patient population. These limitations will be addressed in Part B of the study, which will feature a placebo-controlled design and is planned to enroll a larger number of participants, approximately 330 adult and adolescent patients.

For more insight into the patient's burden/epidemiology, treatment, and changing market landscape-related advancements, refer to Sickle Cell Disease Market Insight, Epidemiology and Market Forecast – 2034 report